SCI Members' News index

Fine Chemicals Group

Problematic proteinases

HIV proteinase - NIST

John Kay of Cardiff University, UK, opened with a plenary overview of aspartic proteinases and laid down the gauntlet to the pharmaceutical industry to continue the fight against a plethora of nasty diseases that are a consequence of over-active proteinases. Rather startlingly, Kay commented that, of the 300 enzyme inhibitor drugs on the market, only seven actually target proteinases. Perhaps the eighth proteinase drug was the subject of the next presentation given by Jürgen Maibaum (Novartis). Maibaum described the discovery and development of the renin inhibitor Aliskiren, which reduces hypertension and has been submitted to the US Food and Drug Administration for approval.

The therapeutic theme was then switched to discovery programmes targeting Alzheimer’s disease. Philip Edwards (AstraZeneca) and Hemaka Rajapakse (Merck) described complementary approaches to β-secretase (BACE) inhibition. Edwards demonstrated the power of fragment-based x-ray crystallography to identify hits and optimise them into potent leads very rapidly. Rajapakse discussed how a five-million-compound high-throughput screen resulted in just one hit that was good enough for optimisation. James Audia (Lilly) then provided details of an alternative approach to slow the progression of Alzheimer’s via inhibition of γ-secretase.

In the first of three lectures on metalloenzymes, David Hepworth (Pfizer) described the structure-based design of neutral endopeptidase inhibitors targeting female sexual arousal disorder. Stephen Martin (GSK) provided the only talk at this meeting on matrix metalloproteinase (MMP) inhibition with MMP-13 being investigated for chronic obstructive pulmonary disorder. The session was then closed by Mark Bunnage (Pfizer) who discussed the potential for inhibition of thrombin activatable fibrinolysis inhibitor (TAFIa) as a treatment for thrombosis. All three talks highlighted a move away from the traditional hydroxamic acid functional group as the metal-binding warhead.

Martin Stahl (Roche) provided an insight into the role of molecular modelling in the quest for serine inhibitors, focusing on factor VIIa and dipeptidyl peptidase IV (DPP-IV). The latter theme was developed by Patrizio Mattei (Roche) who illustrated how structural biology, molecular modelling, synthetic and medicinal chemistry combined efficiently and effectively on the DPP-IV programme to generate, realise and refine ideas into compounds targeting type II diabetes.

Mimi Quan (BMS) returned to the coagulation cascade, describing the synthesis of factor Xa inhibitors. Again, structure-driven drug design was a key theme in this presentation but Quan was quick to highlight the limitations of crystal structures. The next presentation gave further support to the importance of iterative rounds of x-ray crystallography and synthesis to increase understanding of proteinase targets. Michael Graupe (Celera) discussed a structure-based approach to inhibitors of the cysteine proteinase cathepsin S.

HIV proteinase - NIST

Selective cathepsin K inhibitors, which may have potential for the treatment of osteoporosis, were described by Eva Altmann (Novartis). This was followed by Robert Marquis (GSK) who introduced a different series of cathepsin K compounds that could be modified to inhibit cathepsin L selectively. The use of chemical matter as biological tools helped to resolve which of these enzymes is the most important in the bone resorption process (which turned out to be K).

In the four previous proteinase meetings it was apparent how challenging this class of enzymes is. In fact, Steve Swallow (AstraZeneca) remarked beforehand that proteinases are tricky targets. But by the end of day two the outlook was much brighter and Andrew Faller (Lilly) was optimistic about our ability to transfer potent proteinase inhibitors into drugs.